SIR-2.3/SIRT4 loss enhances proteostasis and neuronal resilience via AMPK-induced autophagy in Huntington’s disease models

Autores de IIS La Fe

• Cristina Trujillo Del Rio

  Autor

• Julia Tortajada Pérez

  Autor

• Mar Collado Pérez

  Autor

• 

  Agustín Gerardo Lahoz Rodríguez

  Autor

• Marta Isabel Roca Marugán

  Autor

• 

  José María Millán Salvador

  Autor

• Andrea Del Valle Carranza Figueroa

  Autor

• Rafael Vázquez Manrique

  Autor

Participantes ajenos a IIS La Fe

• Koyuncu, S.
• Gómez-Escribano, A.P.
• Mora, C.
• Néri, C.
• Dos Ramos, Y.
• Vílchez, D.

Grupos

• 

  Biomedicina Molecular, Celular y Genómica

• Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin gene resulting in an extended polyglutamine (polyQ) stretch in the protein, which is prone to aggregation and toxicity. In addition to a proteostasis imbalance, growing evidence highlights the role of mitochondrial dysfunction in HD progression. Here we explore the role of SIR-2.3/SIRT4, a mitochondrial sirtuin, in polyQ-expanded peptides and mutant huntingtin (mHTT) toxicity using C. elegans and mammalian models. Notably, loss of sir-2.3 function results in neuronal protection mediated by AMPK activation and enhanced autophagy. These neuroprotective effects require the transcription factors DAF-16/FOXO and NHR-49, which regulate autophagy and metabolism. To explore the translational potential of these findings, we used soft ATP synthase inhibitors to mimic sir-2.3 ablation, successfully reducing mHTT-induced neuronal toxicity. These results identify the SIRT4-AMPK axis as a critical regulator linking mitochondrial metabolism, autophagy, and neuronal homeostasis in HD. These findings not only advance our understanding of HD pathogenesis but also offer promising therapeutic targets for restoring proteostasis and neuronal resilience capacity against neurodegenerative diseases. © The Author(s) 2026.

Keywords

• huntingtin; polyglutamine; proton transporting adenosine triphosphate synthase; sirtuin; transcription factor; adult; animal cell; animal experiment; animal model; animal tissue; article; autophagy (cellular); Caenorhabditis elegans; controlled study; human; human cell; Huntington chorea; mitochondrial respiration; mouse; nerve cell; neuroprotection; neurotoxicity; nonhuman; protein homeostasis